Ferroptosis targeting natural compounds as a promising approach for developing potent liver cancer agents.

Liver cancer is the second leading cause of cancer-related death worldwide. However, treatment options, including surgical resection, transplantation, and molecular drug therapies, are of limited effectiveness. Recent studies have demonstrated that suppressing ferroptosis might be a pivotal signal for liver cancer initiation, thus providing a new way to combat liver cancer. Ferroptosis is a distinct form of controlled cell death that differs from conventional cell death routes like apoptosis, necrosis, and pyroptosis. It results from intracellular iron overload, which raises iron-dependent reactive oxygen species. This, in turn, leads to the accumulation of lipid peroxides that further result in oxidative damage to cell membranes, disrupt normal functioning, and ultimately speed up the ferroptosis phenomenon. Ferroptosis regulation is intricately linked to cellular physiological processes, encompassing iron metabolism, lipid metabolism, and the equilibrium between oxygen-free radical reactions and lipid peroxidation. This review intends to summarize the natural compounds targeting ferroptosis in liver cancer to offer new therapeutic ideas for liver cancer. Furthermore, it serves as the foundation for identifying and applying chemical medicines and natural chemicals that target ferroptosis to treat liver cancer efficiently.

Recent Advances in Drug Delivery Systems Targeting Insulin Signalling for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the accumulation of neurofibrillary tangles and amyloid-ß plaques. Recent research has unveiled the pivotal role of insulin signaling dysfunction in the pathogenesis of AD. Insulin, once thought to be unrelated to brain function, has emerged as a crucial factor in neuronal survival, synaptic plasticity, and cognitive processes. Insulin and the downstream insulin signaling molecules are found mainly in the hippocampus and cortex. Some molecules responsible for dysfunction in insulin signaling are GSK-3ß, Akt, PI3K, and IRS. Irregularities in insulin signaling or insulin resistance may arise from changes in the phosphorylation levels of key molecules, which can be influenced by both stimulation and inactivity. This, in turn, is believed to be a crucial factor contributing to the development of AD, which is characterized by oxidative stress, neuroinflammation, and other pathological hallmarks. Furthermore, this route is known to be indirectly influenced by Nrf2, NF-κB, and the caspases. This mini-review delves into the intricate relationship between insulin signaling and AD, exploring how disruptions in this pathway contribute to disease progression. Moreover, we examine recent advances in drug delivery systems designed to target insulin signaling for AD treatment. From oral insulin delivery to innovative nanoparticle approaches and intranasal administration, these strategies hold promise in mitigating the impact of insulin resistance on AD. This review consolidates current knowledge to shed light on the potential of these interventions as targeted therapeutic options for AD.

Mechanistic insights into the potential role of dietary polyphenols and their nanoformulation in the management of Alzheimer's disease.

Alzheimer's disease (AD) is a very common neurodegenerative disorder associated with memory loss and a progressive decline in cognitive activity. The two major pathophysiological factors responsible for AD are amyloid plaques (comprising amyloid-beta aggregates) and neurofibrillary tangles (consisting of hyperphosphorylated tau protein). Polyphenols, a class of naturally occurring compounds, are immensely beneficial for the treatment or management of various disorders and illnesses. Naturally occurring sources of polyphenols include plants and plant-based foods, such as fruits, herbs, tea, vegetables, coffee, red wine, and dark chocolate. Polyphenols have unique properties, such as being the major source of anti-oxidants and possessing anti-aging and anti-cancerous properties. Currently, dietary polyphenols have become a potential therapeutic approach for the management of AD, depending on various research findings. Dietary polyphenols can be an effective strategy to tackle multifactorial events that occur with AD. For instance, naturally occurring polyphenols have been reported to exhibit neuroprotection by modulating the Aß biogenesis pathway in AD. Many nanoformulations have been established to enhance the bioavailability of polyphenols, with nanonization being the most promising. This review comprehensively provides mechanistic insights into the neuroprotective potential of dietary polyphenols in treating AD. It also reviews the usability of dietary polyphenol as nanoformulation for AD treatment.

Psychedelics for alzheimer's disease-related dementia: Unveiling therapeutic possibilities and pathways.

Psychedelics have traditionally been used for spiritual and recreational purposes, but recent developments in psychotherapy have highlighted their potential as therapeutic agents. These compounds, which act as potent 5-hydroxytryptamine (5HT) agonists, have been recognized for their ability to enhance neural plasticity through the activation of the serotoninergic and glutamatergic systems. However, the implications of these findings for the treatment of neurodegenerative disorders, particularly dementia, have not been fully explored. In recent years, studies have revealed the modulatory and beneficial effects of psychedelics in the context of dementia, specifically Alzheimer's disease (AD)-related dementia, which lacks a definitive cure. Psychedelics such as N,N-dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), and Psilocybin have shown potential in mitigating the effects of this debilitating disease. These compounds not only target neurotransmitter imbalances but also act at the molecular level to modulate signalling pathways in AD, including the brain-derived neurotrophic factor signalling pathway and the subsequent activation of mammalian target of rapamycin and other autophagy regulators. Therefore, the controlled and dose-dependent administration of psychedelics represents a novel therapeutic intervention worth exploring and considering for the development of drugs for the treatment of AD-related dementia. In this article, we critically examined the literature that sheds light on the therapeutic possibilities and pathways of psychedelics for AD-related dementia. While this emerging field of research holds great promise, further studies are necessary to elucidate the long-term safety, efficacy, and optimal treatment protocols. Ultimately, the integration of psychedelics into the current treatment paradigm may provide a transformative approach for addressing the unmet needs of individuals living with AD-related dementia and their caregivers.

Unveiling the impact of aging on BBB and Alzheimer's disease: Factors and therapeutic implications.

Alzheimer's disease (AD) is a highly prevalent neurodegenerative condition that has devastating effects on individuals, often resulting in dementia. AD is primarily defined by the presence of extracellular plaques containing insoluble ß-amyloid peptide (Aß) and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein (P-tau). In addition, individuals afflicted by these age-related illnesses experience a diminished state of health, which places significant financial strain on their loved ones. Several risk factors play a significant role in the development of AD. These factors include genetics, diet, smoking, certain diseases (such as cerebrovascular diseases, obesity, hypertension, and dyslipidemia), age, and alcohol consumption. Age-related factors are key contributors to the development of vascular-based neurodegenerative diseases such as AD. In general, the process of aging can lead to changes in the immune system's responses and can also initiate inflammation in the brain. The chronic inflammation and the inflammatory mediators found in the brain play a crucial role in the dysfunction of the blood-brain barrier (BBB). Furthermore, maintaining BBB integrity is of utmost importance in preventing a wide range of neurological disorders. Therefore, in this review, we discussed the role of age and its related factors in the breakdown of the blood-brain barrier and the development of AD. We also discussed the importance of different compounds, such as those with anti-aging properties, and other compounds that can help maintain the integrity of the blood-brain barrier in the prevention of AD. This review builds a strong correlation between age-related factors, degradation of the BBB, and its impact on AD.

Biological Synthesis, Characterization, and Therapeutic Potential of S. commune-Mediated Gold Nanoparticles.

Green-synthesized gold nanoparticles demonstrate several therapeutic benefits due to their safety, non-toxicity, accessibility, and ecological acceptance. In our study, gold nanoparticles (AuNPs) were created using an extracellular extract from the fungus Schizophyllum commune (S. commune). The reaction color was observed to be a reddish pink after a 24 h reaction, demonstrating the synthesis of the nanoparticles. The myco-produced nanoparticles were investigated using transmission electron microscopy (TEM), dynamic light scattering (DLS), and UV-visible spectroscopy. The TEM pictures depicted sphere-like shapes with sizes ranging from 60 and 120 nm, with an average diameter of 90 nm, which is in agreement with the DLS results. Furthermore, the efficiency of the AuNPs' antifungal and cytotoxic properties, as well as their production of intracellular ROS, was evaluated. Our findings showed that the AuNPs have strong antifungal effects against Trichoderma sp. and Aspergillus flavus at increasing doses. Additionally, the AuNPs established a dose-dependent activity against human alveolar basal epithelial cells with adenocarcinoma (A549), demonstrating the potency of synthesized AuNPs as a cytotoxic agent. After 4 h of incubation with AuNPs, a significant increase in intracellular ROS was observed in cancer cells. Therefore, these metallic AuNPs produced by fungus (S. commune) can be used as an effective antifungal, anticancer, and non-toxic immunomodulatory delivery agent.

Pharmacophore-Based Screening, Molecular Docking, and Dynamic Simulation of Fungal Metabolites as Inhibitors of Multi-Targets in Neurodegenerative Disorders.

Neurodegenerative disorders, such as Alzheimer's disease (AD), negatively affect the economic and psychological system. For AD, there is still a lack of disease-altering treatments and promising cures due to its complex pathophysiology. In this study, we computationally screened the natural database of fungal metabolites against three known therapeutic target proteins of AD. Initially, a pharmacophore-based, drug-likeness category was employed for screening, and it filtered the 14 (A-N) best hits out of 17,544 fungal metabolites. The 14 best hits were docked individually against GSK-3ß, the NMDA receptor, and BACE-1 to investigate the potential of finding a multitarget inhibitor. We found that compounds B, F, and L were immuno-toxic, whereas E, H, I, and J had a higher LD50 dose (5000 mg/kg). Among the examined metabolites, the Bisacremine-C (compound I) was found to be the most active molecule against GSK-3ß (ΔG: -8.7 ± 0.2 Kcal/mol, Ki: 2.4 × 106 M-1), NMDA (ΔG: -9.5 ± 0.1 Kcal/mol, Ki: 9.2 × 106 M-1), and BACE-1 (ΔG: -9.1 ± 0.2 Kcal/mol, Ki: 4.7 × 106 M-1). It showed a 25-fold higher affinity with GSK-3ß, 6.3-fold higher affinity with NMDA, and 9.04-fold higher affinity with BACE-1 than their native ligands, respectively. Molecular dynamic simulation parameters, such as RMSD, RMSF, Rg, and SASA, all confirmed that the overall structures of the targeted enzymes did not change significantly after binding with Bisacremine-C, and the ligand remained inside the binding cavity in a stable conformation for most of the simulation time. The most significant hydrophobic contacts for the GSK-3ß-Bisacremine-C complex are with ILE62, VAL70, ALA83, and LEU188, whereas GLN185 is significant for H-bonds. In terms of hydrophobic contacts, TYR184 and PHE246 are the most important, while SER180 is vital for H-bonds in NMDA-Bisacremine-C. THR232 is the most crucial for H-bonds in BACE-1-Bisacremine-C and ILE110-produced hydrophobic contacts. This study laid a foundation for further experimental validation and clinical trials regarding the biopotency of Bisacremine-C.

Oxidative Stress and Natural Antioxidants: Back and Forth in the Neurological Mechanisms of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by the progressive degeneration of neuronal cells. With the increase in aged population, there is a prevalence of irreversible neurodegenerative changes, causing a significant mental, social, and economic burden globally. The factors contributing to AD are multidimensional, highly complex, and not completely understood. However, it is widely known that aging, neuroinflammation, and excessive production of reactive oxygen species (ROS), along with other free radicals, substantially contribute to oxidative stress and cell death, which are inextricably linked. While oxidative stress is undeniably important in AD, limiting free radicals and ROS levels is an intriguing and potential strategy for deferring the process of neurodegeneration and alleviating associated symptoms. Therapeutic compounds from natural sources have recently become increasingly accepted and have been effectively studied for AD treatment. These phytocompounds are widely available and a multitude of holistic therapeutic efficiencies for treating AD owing to their antioxidant, anti-inflammatory, and biological activities. Some of these compounds also function by stimulating cholinergic neurotransmission, facilitating the suppression of beta-site amyloid precursor protein-cleaving enzyme 1, α-synuclein, and monoamine oxidase proteins, and deterring the occurrence of AD. Additionally, various phenolic, flavonoid, and terpenoid phytocompounds have been extensively described as potential palliative agents for AD progression. Preclinical studies have shown their involvement in modulating the cellular redox balance and minimizing ROS formation, displaying them as antioxidant agents with neuroprotective abilities. This review emphasizes the mechanistic role of natural products in the treatment of AD and discusses the various pathological hypotheses proposed for AD.

Antioxidant, LC-MS Analysis, and Cholinesterase Inhibitory Potentials of Phoenix dactylifera Cultivar Khudari: An In Vitro Enzyme Kinetics and In Silico Study.

We evaluated the therapeutic potentials of Khudari fruit pulp, a functional food and cultivar of Phoenix dactylifera, against neurological disorders. Our results demonstrate a good amount of phytochemicals (total phenolic content: 17.77 ± 8.21 µg GA/mg extract) with a high antioxidant potential of aqueous extract (DPPH assay IC50 = 235.84 ± 11.65 µg/mL) and FRAP value: 331.81 ± 4.56 µmol. Furthermore, the aqueous extract showed the marked inhibition of cell-free acetylcholinesterase (electric eel) with an IC50 value of 48.25 ± 2.04 µg/mL, and an enzyme inhibition kinetics study revealed that it exhibits mixed inhibition. Thereafter, we listed the 18 best-matched phytochemical compounds present in aqueous extract through LC/MS analysis. The computational study revealed that five out of eighteen predicted compounds can cross the BBB and exert considerable aqueous solubility. where 2-{5-[(1E)-3-methylbuta-1,3-dien-1-yl]-1H-indol-3-yl}ethanol (MDIE) indicates an acceptable LD50. value. A molecular docking study exhibited that the compounds occupied the key residues of acetylcholinesterase with ΔG range between -6.91 and -9.49 kcal/mol, where MDIE has ∆G: -8.67 kcal/mol, which was better than that of tacrine, ∆G: -8.25 kcal/mol. Molecular dynamics analyses of 100 ns supported the stability of the protein-ligand complexes analyzed through RMSD, RMSF, Rg, and SASA parameters. TRP_84 and GLY_442 are the most critical hydrophobic contacts for the complex, although GLU_199 is important for H-bonds. Prime/MM-GBSA showed that the protein-ligand complex formed a stable confirmation. These findings suggest that the aqueous extract of Khudari fruit pulp has significant antioxidant and acetylcholinesterase inhibition potentials, and its compound, MDIE, forms stably with confirmation with the target protein, though this fruit of Khudari dates can be a better functional food for the treatment of Alzheimer's disease. Further investigations are needed to fully understand the therapeutic role of this plant-based compound via in vivo study.

Myco-Synthesis of Silver Nanoparticles and Their Bioactive Role against Pathogenic Microbes.

Nanotechnology based on nanoscale materials is rapidly being used in clinical settings, particularly as a new approach for infectious illnesses. Recently, many physical/chemical approaches utilized to produce nanoparticles are expensive and highly unsafe to biological species and ecosystems. This study demonstrated an environmentally friendly mode of producing nanoparticles (NPs) where Fusarium oxysporum has been employed for generation of silver nanoparticles (AgNPs), which were further tested for their antimicrobial potentials against a variety of pathogenic microorganisms. The characterization of NPs was completed by UV-Vis spectroscopy, DLS and TEM, where it has been found that the NPs were mostly globular, with the size range of 50 to 100 nm. The myco-synthesized AgNPs showed prominent antibacterial potency observed as zone of inhibition of 2.6 mm, 1.8 mm, 1.5 mm, and 1.8 mm against Vibrio cholerae, Streptococcus pneumoniae, Klebsiella pneumoniae and Bacillus anthracis, respectively, at 100 µM. Similarly, at 200 µM for A. alternata, A. flavus and Trichoderma have shown zone of inhibition as 2.6 mm, 2.4 mm, and 2.1 mm, respectively. Moreover, SEM analysis of A. alternata confirmed the hyphal damage where the layers of membranes were torn off, and further EDX data analysis showed the presence of silver NPs, which might be responsible for hyphal damage. The potency of NPs may be related with the capping of fungal proteins that are produced extracellularly. Thus, these AgNPs may be used against pathogenic microbes and play a beneficial role against multi-drug resistance.

Multitargeted Virtual Screening and Molecular Simulation of Natural Product-like Compounds against GSK3ß, NMDA-Receptor, and BACE-1 for the Management of Alzheimer's Disease.

The complexity of Alzheimer's disease (AD) and several side effects of currently available medication inclined us to search for a novel natural cure by targeting multiple key regulatory proteins. We initially virtually screened the natural product-like compounds against GSK3ß, NMDA receptor, and BACE-1 and thereafter validated the best hit through molecular dynamics simulation (MDS). The results demonstrated that out of 2029 compounds, only 51 compounds exhibited better binding interactions than native ligands, with all three protein targets (NMDA, GSK3ß, and BACE) considered multitarget inhibitors. Among them, F1094-0201 is the most potent inhibitor against multiple targets with binding energy -11.7, -10.6, and -12 kcal/mol, respectively. ADME-T analysis results showed that F1094-0201 was found to be suitable for CNS drug-likeness in addition to their other drug-likeness properties. The MDS results of RMSD, RMSF, Rg, SASA, SSE and residue interactions indicated the formation of a strong and stable association in the complex of ligands (F1094-0201) and proteins. These findings confirm the F1094-0201's ability to remain inside target proteins' binding pockets while forming a stable complex of protein-ligand. The free energies (MM/GBSA) of BACE-F1094-0201, GSK3ß-F1094-0201, and NMDA-F1094-0201 complex formation were -73.78 ± 4.31 kcal mol-1, -72.77 ± 3.43 kcal mol-1, and -52.51 ± 2.85 kcal mol-1, respectively. Amongst the target proteins, F1094-0201 have a more stable association with BACE, followed by NMDA and GSK3ß. These attributes of F1094-0201 indicate it as a possible option for the management of pathophysiological pathways associated with AD.

Antibacterial efficacy of synthesized silver nanoparticles of Microbacterium proteolyticum LA2(R) and Streptomyces rochei LA2(O) against biofilm forming meningitis causing microbes.

Actinobacteria obtained from the least explored Indian regions were studied for their ability to suppress meningitis-causing bacteria in nanoparticle form. Drug-resistant bacteria and long-term treatment with different medications make meningitis control complicated. Thus, new meningitis drugs are required to combat MDR bacteria. In this study, secondary metabolites isolated from actinomycetes strains, Microbacterium proteolyticum LA2(R) and Streptomyces rochei LA2(O), were employed to synthesize silver nanoparticles (AgNPs) at 37 °C for seven days incubation. UV-Vis spectroscopy, TEM, FTIR, and HPLC studies were used for the confirmation of the synthesis of AgNPs. Furthermore, these NPs demonstrated antibacterial and antibiofilm activities against meningitis-causing bacteria. The average size of LA2(R) and LA2(O) isolated secondary metabolites mediated AgNPs was observed to be 27 ± 1and 29 ± 2 nm by TEM analysis. FTIR study of RAgNPs and OAgNPs revealed that presence of peaks with positions of 1637.17 cm1 and 1636.10 cm1 for C=O amide group appearances in the amide I linkage. These NPs were effective against bacterial pathogens such as S. pneumoniae, H. influenzae, and N. meningitidis and confirmed by their MICs, i.e., 109.4, 120.60, and 138.80 µg/ml of RAgNPs and 105.80, 114.40 and 129.06 µg/ml of OAgNPs, respectively. Additionally, the production of biofilms is impeded by these nanoparticles on S. pneumoniae, H. influenzae, and N. meningitidis by 73.14%, 71.89% and 64.81%, respectively. These findings confirm the potential role of synthesized AgNPs against biofilm forming meningitis causing Multidrug resistance (MDR) microbes.

Husk-like Zinc Oxide Nanoparticles Induce Apoptosis through ROS Generation in Epidermoid Carcinoma Cells: Effect of Incubation Period on Sol-Gel Synthesis and Anti-Cancerous Properties.

This study effectively reports the influence of experimental incubation period on the sol-gel production of husk-like zinc oxide nanoparticles (ZNPs) and their anti-cancerous abilities. The surface morphology of ZNPs was studied with the help of SEM. With the use of TEM, the diameter range of the ZNPs was estimated to be ~86 and ~231 nm for ZNPA and ZNPB, prepared by incubating zinc oxide for 2 and 10 weeks, respectively. The X-ray diffraction (XRD) investigation showed that ZNPs had a pure wurtzite crystal structure. On prolonging the experimental incubation, a relative drop in aspect ratio was observed, displaying a distinct blue-shift in the UV-visible spectrum. Furthermore, RBC lysis assay results concluded that ZNPA and ZNPB both demonstrated innoxious nature. As indicated by MTT assay, reactive oxygen species (ROS) release, and chromatin condensation investigations against the human epidermoid carcinoma (HEC) A431 cells, ZNPB demonstrated viable relevance to chemotherapy. Compared to ZNPB, ZNPA had a slightly lower IC50 against A431 cells due to its small size. This study conclusively describes a simple, affordable method to produce ZNP nano-formulations that display significant cytotoxicity against the skin cancer cell line A431, suggesting that ZNPs may be useful in the treatment of cancer.

Elucidations of Molecular Mechanism and Mechanistic Effects of Environmental Toxicants in Neurological Disorders.

Due to rising environmental and global public health concerns associated with environmental contamination, human populations are continually being exposed to environmental toxicants, including physical chemical mutagens widespread in our environment causing adverse consequences and inducing a variety of neurological disorders in humans. Physical mutagens comprise ionizing and non-ionizing radiation, such as UV rays, IR rays, X-rays, which produces a broad spectrum of neuronal destruction, including neuroinflammation, genetic instability, enhanced oxidative stress driving mitochondrial damage in the human neuronal antecedent cells, cognitive impairment due to alterations in neuronal function, especially in synaptic plasticity, neurogenesis repression, modifications in mature neuronal networks drives to enhanced neurodegenerative risk. Chemical Mutagens including alkylating agents (EMS, NM, MMS, and NTG), Hydroxylamine, nitrous acid, sodium azide, halouracils are the major toxic mutagen in our environment and have been associated with neurological disorders. These chemical mutagens create dimers of pyrimidine that cause DNA damage that leads to ROS generation producing mutations, chromosomal abnormalities, genotoxicity which leads to increased neurodegenerative risk. The toxicity of four heavy metal including Cd, As, Pb, Hg is mostly responsible for complicated neurological disorders in humans. Cadmium exposure can enhance the permeability of the BBB and penetrate the brain, driving brain intracellular accumulation, cellular dysfunction, and cerebral edema. Arsenic exerts its toxic effect by induction of ROS production in neuronal cells. In this review, we summarize the molecular mechanism and mechanistic effects of mutagens in the environment and their role in multiple neurological disorders.

Prevalence of rheumatoid arthritis and diagnostic validity of a prediction score, in patients visiting orthropedic clinics in the Madinah region of Saudi Arabia: a retrospective cross-sectional study.

Introduction: In Saudi Arabia, the epidemiology of rheumatoid arthritis (RA) is not well studied and is marked by inconsistencies in clinical diagnosis. Therefore, in this study, we explored the prevalence, clinical characteristics, and diagnostic validity of a prediction score based upon disease markers in orthropedic clinics' patients in the Madinah region of Saudi Arabia. Method: The clinical data for this retrospective cross-sectional study were retrieved from the database registry of orthopedic clinics in selected hospitals of the Medinah province of Saudi Arabia. Sociodemographic features, disease markers and the clinical characteristics were collected for a period of 6 months, from December 1, 2020, to May 31, 2021. The prediction score was generated from the sum of disease markers, coded as dichotomous variables. Results: The total sample size of our study was 401. The prevalence of RA in the study subjects (n = 401) was 14.46% (n = 58). Among RA patients, the majority were females (60.3%). Painful joints (69%) and swollen joints (51.7%) were the most common clinical complaints among RA patients. RA patients suffered from arthritis (51.7%) and experienced fatigue (46.6%), weight loss (44.8%), and loss of appetite (41.4%). Diabetes (55.2%) was the most common comorbidity in the RA patients. The sensitivity and specificity of the prediction score at the criterion score of 2.5 were 67.3% and 63.0%, respectively. The area under the curve was 0.69 (95% CI [0.62-0.76]). Conclusion: There was a moderately high prevalence of RA in patients visiting the orthropedic clinics of the selected hospitals of Madinah region of Saudi Arabia. The diagnostic validity of the prediction score, though promising, was slightly lower than the acceptable range.

In silico investigations identified Butyl Xanalterate to competently target CK2α (CSNK2A1) for therapy of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is an incurable malignancy of B-cells. In this study, bioinformatics analyses were conducted to identify possible pathogenic roles of CK2α, which is a protein encoded by CSNK2A1, in the progression and aggressiveness of CLL. Furthermore, various computational tools were used to search for a competent inhibitor of CK2α from fungal metabolites that could be proposed for CLL therapy. In CLL patients, high-expression of CSNK2A1 was associated with early need for therapy (n = 130, p < 0.0001) and short overall survival (OS; n = 107, p = 0.005). Consistently, bioinformatics analyses showed CSNK2A1 to associate with/play roles in CLL proliferation and survival-dependent pathways. Furthermore, PPI network analysis identified interaction partners of CK2α (PPI enrichment p value = 1 × 10-16) that associated with early need for therapy (n = 130, p < 0.003) and have been known to heavily impact on the progression of CLL. These findings constructed a rational for targeting CK2α for CLL therapy. Consequently, computational analyses reported 35 fungal metabolites out of 5820 (filtered from 19,967 metabolites) to have lower binding energy (ΔG: - 10.9 to - 11.7 kcal/mol) and better binding affinity (Kd: 9.77 × 107 M-1 to 3.77 × 108 M-1) compared with the native ligand (ΔG: - 10.8, Kd: 8.3 × 107 M--1). Furthermore, molecular dynamics simulation study established that Butyl Xanalterate-CK2α complex continuously remained stable throughout the simulation time (100 ns). Moreover, Butyl Xanalterate interacted with most of the catalytic residues, where complex was stabilized by more than 65% hydrogen bond interactions, and a significant hydrophobic interaction with residue Phe113. Here, high-expression of CSNK2A1 was implicated in the progression and poor prognosis of CLL, making it a potential therapeutic target in the disease. Butyl Xanalterate showed stable and strong interactions with CK2α, thus we propose it as a competitive inhibitor of CK2α for CLL therapy.

Epigenetic factors in breast cancer therapy.

Epigenetic modifications are inherited differences in cellular phenotypes, such as cell gene expression alterations, that occur during somatic cell divisions (also, in rare circumstances, in germ line transmission), but no alterations to the DNA sequence are involved. Histone alterations, polycomb/trithorax associated proteins, short non-coding or short RNAs, long non-coding RNAs (lncRNAs), & DNA methylation are just a few biological processes involved in epigenetic events. These various modifications are intricately linked. The transcriptional potential of genes is closely conditioned by epigenetic control, which is crucial in normal growth and development. Epigenetic mechanisms transmit genomic adaptation to an environment, resulting in a specific phenotype. The purpose of this systematic review is to glance at the roles of Estrogen signalling, polycomb/trithorax associated proteins, DNA methylation in breast cancer progression, as well as epigenetic mechanisms in breast cancer therapy, with an emphasis on functionality, regulatory factors, therapeutic value, and future challenges.

ROCK2 inhibition: A futuristic approach for the management of Alzheimer's disease.

Neurons depend on mitochondrial functions for membrane excitability, neurotransmission, and plasticity. Mitochondrial dynamics are important for neural cell maintenance. To maintain mitochondrial homeostasis, lysosomes remove dysfunctional mitochondria through mitophagy. Mitophagy promotes mitochondrial turnover and prevents the accumulation of dysfunctional mitochondria. In many neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), mitophagy is disrupted in neurons. Mitophagy is regulated by several proteins; recently, Rho-associated coiled-coil containing protein kinase 2 (ROCK2) has been suggested to negatively regulate the Parkin-dependent mitophagy pathway. Thus, ROCK2 inhibition may be a promising therapy for NDDs. This review summarizes the mitophagy pathway, the role of ROCK2 in Parkin-dependent mitophagy regulation, and mitophagy impairment in the pathology of AD. We further discuss different ROCK inhibitors (synthetic drugs, natural compounds, and gene therapy-based approaches) and examine their effects on triggering neuronal growth and neuroprotection in AD and other NDDs. This comprehensive overview of the role of ROCK in mitophagy inhibition provides a possible explanation for the significance of ROCK inhibitors in the therapeutic management of AD and other NDDs.

Oleuropein as a Potent Compound against Neurological Complications Linked with COVID-19: A Computational Biology Approach.

The association of COVID-19 with neurological complications is a well-known fact, and researchers are endeavoring to investigate the mechanistic perspectives behind it. SARS-CoV-2 can bind to Toll-like receptor 4 (TLR-4) that would eventually lead to α-synuclein aggregation in neurons and stimulation of neurodegeneration pathways. Olive leaves have been reported as a promising phytotherapy or co-therapy against COVID-19, and oleuropein is one of the major active components of olive leaves. In the current study, oleuropein was investigated against SARS-CoV-2 target (main protease 3CLpro), TLR-4 and Prolyl Oligopeptidases (POP), to explore oleuropein potency against the neurological complications associated with COVID-19. Docking experiments, docking validation, interaction analysis, and molecular dynamic simulation analysis were performed to provide insight into the binding pattern of oleuropein with the three target proteins. Interaction analysis revealed strong bonding between oleuropein and the active site amino acid residues of the target proteins. Results were further compared with positive control lopinavir (3CLpro), resatorvid (TLR-4), and berberine (POP). Moreover, molecular dynamic simulation was performed using YASARA structure tool, and AMBER14 force field was applied to examine an 100 ns trajectory run. For each target protein-oleuropein complex, RMSD, RoG, and total potential energy were estimated, and 400 snapshots were obtained after each 250 ps. Docking analyses showed binding energy as -7.8, -8.3, and -8.5 kcal/mol for oleuropein-3CLpro, oleuropein-TLR4, and oleuropein-POP interactions, respectively. Importantly, target protein-oleuropein complexes were stable during the 100 ns simulation run. However, an experimental in vitro study of the binding of oleuropein to the purified targets would be necessary to confirm the present study outcomes.

Dithymoquinone Analogues as Potential Candidate(s) for Neurological Manifestation Associated with COVID-19: A Therapeutic Strategy for Neuro-COVID.

The COVID-19 era has prompted several researchers to search for a linkage between COVID-19 and its associated neurological manifestation. Toll-like receptor 4 (TLR-4) acts as one such connecting link. spike protein of SARS-CoV-2 can bind either to ACE-2 receptors or to TLR-4 receptors, leading to aggregation of α-synuclein and neurodegeneration via the activation of various cascades in neurons. Recently, dithymoquinone has been reported as a potent multi-targeting candidate against SARS-CoV-2. Thus, in the present study, dithymoquinone and its six analogues were explored to target 3CLpro (main protease of SARS-CoV-2), TLR4 and PREP (Prolyl Oligopeptidases) by using the molecular docking and dynamics approach. Dithymoquinone (DTQ) analogues were designed in order to investigate the effect of different chemical groups on its bioactivity. It is noteworthy to mention that attention was given to the feasibility of synthesizing these analogues by a simple photo-dimerisation reaction. The DTQ analogue containing the 4-fluoroaniline moiety [Compound (4)] was selected for further analysis by molecular dynamics after screening via docking-interaction analyses. A YASARA structure tool built on the AMBER14 force field was used to analyze the 100 ns trajectory by taking 400 snapshots after every 250 ps. Moreover, RMSD, RoG, potential energy plots were successfully obtained for each interaction. Molecular docking results indicated strong interaction of compound (4) with 3CLpro, TLR4 and PREP with a binding energy of -8.5 kcal/mol, -10.8 kcal/mol and -9.5 kcal/mol, respectively, which is better than other DTQ-analogues and control compounds. In addition, compound (4) did not violate Lipinski's rule and showed no toxicity. Moreover, molecular dynamic analyses revealed that the complex of compound (4) with target proteins was stable during the 100 ns trajectory. Overall, the results predicted that compound (4) could be developed into a potent anti-COVID agent with the ability to mitigate neurological manifestations associated with COVID-19.